Activation of Human Bronchial Epithelial Cells by Inflammatory Cytokines IL-27 and TNF-alpha: Implications for Immunopathophysiology of Airway Inflammation

Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
Journal of Cellular Physiology (Impact Factor: 3.84). 06/2010; 223(3):788-97. DOI: 10.1002/jcp.22094
Source: PubMed


Interleukin (IL)-27 is a member of IL-6/IL-12 family cytokines produced by antigen-presenting cells in immune responses. IL-27 can drive the commitment of naive T cells to a T helper type 1 (Th1) phenotype and inhibit inflammation in later phases of infection. Human bronchial epithelial cells have been shown to express IL-27 receptor complex. In this study, we investigated the in vitro effects of IL-27, alone or in combination with inflammatory cytokine tumor necrosis factor (TNF)-alpha on the pro-inflammatory activation of human primary bronchial epithelial cells and the underlying intracellular signaling mechanisms. IL-27 was found to enhance intercellular adhesion molecule 1 (ICAM-1) expression on the surface of human bronchial epithelial cells, and a synergistic effect was observed in the combined treatment of IL-27 and TNF-alpha on the expression of ICAM-1. Although IL-27 did not alter the basal IL-6 secretion from bronchial epithelial cells, it could significantly augment TNF-alpha-induced IL-6 release. These synergistic effects on the up-regulation of ICAM-1 and IL-6 were partially due to the elevated expression of TNF-alpha receptor (p55TNFR) induced by IL-27. Further investigations showed that the elevation of ICAM-1 and IL-6 in human bronchial epithelial cells stimulated by IL-27 and TNF-alpha was differentially regulated by phosphatidylinositol 3-OH kinase (PI3K)-Akt, p38 mitogen-activated protein kinase, and nuclear factor-kappaB pathways. Our results therefore provide a new insight into the molecular mechanisms involved in airway inflammation.

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    • ". PBEC are commonly used as in vitro models for studying the expression of cytokines and chemokines in airway epithelial cells activated by inflammatory mediators. In this study, we used welldifferentiated PBEC in air&ndashliquid interfaces to study the effects of CbpA on the activation of bronchial epithelial cells, because differentiated PBEC are believed to resemble a more physiologically relevant phenotype and to more closely model the in vivo situation [31]. Using nonciliated bronchial epithelial cells, we also found that pneumococcal CbpA could upregulate the expression of ICAM-1, IL-6, CCL2, CXCL1, and CXCL8 in bronchial epithelial cell lines (BEAS-2B cells), similar to the results observed in differentiated PBEC (data not shown). "
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    ABSTRACT: Choline binding protein A (CbpA) is an important adhesin and a determinant of virulence for Streptococcus pneumoniae. Binding to epithelial cells of host mucosal surfaces by pneumococcal CbpA is essential for pneumococcus to initiate colonization and to trigger subsequent invasive pneumococcal infections. In this study, we examined the immunopathologic mechanisms for the activation of human bronchial epithelial cells by CbpA in pneumococcal infections. Adhesion molecules, cytokines, and chemokines were assessed by flow cytometry, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. Intracellular signaling molecules were investigated by enzyme-linked immunosorbent assay or transcription factor assay. CbpA could upregulate cell surface expression of adhesion molecule intercellular adhesion molecule-1 on human bronchial epithelial cells. CbpA could also induce the release of inflammatory cytokine interleukin-6, and chemokines CCL2, CXCL1, and CXCL8 from human bronchial epithelia cells. CbpA-mediated induction of these mediators was differentially regulated by extracellular signal-regulated kinase, c-Jun N-terminal protein kinase, p38-mitogen-activated protein kinase, and nuclear factor-κB pathways. CbpA was also found to participate in the induction of IL-6, CCL2, CXCL1, and CXCL8 in the airways of mice upon intranasal challenge with S. pneumoniae. Our study therefore suggests that pneumococcal CbpA plays an immunopathophysiologic role by activating human bronchial epithelial cells in pneumococcal infections.
    Human immunology 10/2010; 72(1):37-46. DOI:10.1016/j.humimm.2010.10.007 · 2.14 Impact Factor
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    • "It may be due to the lower cell surface expression of TNFRp55 (data not shown), the crucial TNF receptor component for the expression of adhesion molecule ICAM-1 and VCAM-1, on RA-FLS compared with control FLS [45,46]. However, our previous study showed that the synergistic activating effects of IL-27 and TNF-α on bronchial epithelial cells were partially due to the IL-27 up-regulated expression of TNF-α receptor p55TNFR [47]. IL-27 stimulation could also lead to the increased expression of TNF-α and IL-1β in primary human monocytes [14,48]. "
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    ABSTRACT: Interleukin (IL)-27 is a novel member of the IL-6/IL-12 family cytokines that are produced early by antigen-presenting cells in T helper (Th)1-mediated inflammation. Elevated expression of IL-27 has been detected in the synovial membranes and fluid of rheumatoid arthritis (RA). We investigated the in vitro effects of IL-27, alone or in combination with inflammatory cytokine tumor necrosis factor (TNF)-α or IL-1 β on the pro-inflammatory activation of human primary fibroblast-like synoviocytes (FLS) from RA patients and normal control subjects, and the underlying intracellular signaling molecules were determined by intracellular staining using flow cytometry. Significantly higher plasma concentration of IL-27 was found in RA patients (n = 112) than control subjects (n = 46). Both control and RA-FLS constitutively express functional IL-27 receptor heterodimer, gp130 and WSX-1, with more potent IL-27-mediated activation of signal transducers and activators of transcription (STAT)1 in RA-FLS. IL-27 was found to induce significantly higher cell surface expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 and release of inflammatory chemokine IL-6, CCL2, CXCL9, CXCL10 and matrix metalloproteinase-1 of RA-FLS than that of control FLS (all P < 0.05). Moreover, an additive or synergistic effect was observed in the combined treatment of IL-27 and TNF-α or IL-1 β on the surface expression of ICAM-1 and VCAM-1 and the release of CXCL9 and CXCL10 of RA-FLS. Further investigations showed that the expression of ICAM-1, VCAM-1 and chemokines stimulated by IL-27 was differentially regulated by intracellular activation of phosphatidylinositol 3-OH kinase-AKT, c-Jun amino-terminal kinase and Janus kinase pathways. Our results therefore provide a new insight into the IL-27-activated immunopathological mechanisms mediated by distinct intracellular signal transductions in joint inflammation of RA.
    Arthritis research & therapy 07/2010; 12(4):R129. DOI:10.1186/ar3067 · 3.75 Impact Factor
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    ABSTRACT: The role of IL-27 in the pathogenesis of airway inflammatory diseases remains elusive. We, therefore, have studied its concentrations in the sputum and plasma of patients with COPD and patients with pulmonary TB (PTB), and further investigated the mechanism-of-action effects of IL-27 on bronchial epithelial cells in vitro. Human bronchial epithelial cells grown on air-liquid interface culture were activated by IL-27, alone, or in combination with other inflammatory cytokines in the presence or absence of various signaling molecule inhibitors. The expression of CXCL10 was detected by reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). The underlying signaling pathways were studied by intracellular staining using flow cytometry, Western blot, ELISA, or siRNA. Significantly higher sputum and plasma concentrations of IL-27 were found in patients with COPD (n = 34; P < .01 and P < .001, respectively) or patients with PTB (n = 31; P < .01 and P < .001, respectively) than in healthy control subjects (n = 48). Sputum, but not plasma, IL-27 levels in patients with COPD correlated negatively with FEV(1) (r = -0.51, P < .01). Sputum, but not plasma, IL-27 in patients with PTB correlated positively with mycobacterial load in sputum (r = 0.48, P < .05). Further in vitro studies demonstrated that IL-27 could induce gene and protein expression of CXCL10 in bronchial epithelial cells, which was regulated by the activation of the phosphatidylinositol 3-OH kinase (PI3K)-Akt signaling pathway. The production of IL-27 is related to the pathogenesis of COPD and PTB, and IL-27 induces the expression of CXCL10 in bronchial epithelial cells through the activation of the PI3K-Akt signaling pathway.
    Chest 07/2011; 141(1):121-30. DOI:10.1378/chest.10-3297 · 7.48 Impact Factor
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